Abstract

The BRAF serine/threonine kinase is mutated, typically at V600, to remain in the active oncogenic state in a large fraction of melanoma, thyroid cancers, and hairy cell leukemia, and to a lesser extent in a wide spectrum of other cancers, thereby activating the kinases MEK1 and MEK2 to stimulate the MAPK pathway and promote cancer. Excitingly, ATP inhibitors of oncogenic BRAF and MEK provide a survival advantage in metastatic melanoma and early clinical studies suggest that coupling BRAF and MEK kinase inhibitors may be even more effective. Thus, the combination of multiple approaches to inhibit MAPK signaling holds great promise for the treatment of BRAF mutation-positive cancers, especially in terms of overcoming resistance. In this regard, we previously found that copper (Cu) influx enhanced MEK1 phosphorylation of its substrates ERK1/2 through a Cu-MEK1 interaction. We show here that genetic loss of the high affinity Cu transporter Ctr1 or mutations in MEK1 that disrupt Cu binding reduced MAPK signaling and oncogenic BRAFV600E-mediated tumorigenesis, which could be rescued by expressing activated ERK2. Importantly, a Cu chelator used in the treatment of Wilson's disease reduced tumor growth of not only BRAFV600E-transformed cells, but also cells resistant to a BRAF inhibitor. Taken together, these results suggest that Cu-chelation therapy could be repurposed for the treatment of BRAFV600E mutation-positive cancers.